This Program Project has been designed to increase our understanding of the mechanism of sudden cardiac death, its treatment and prevention. Five research proposals served by five core facilities are designed to address questions relative to an understanding of causes and effects of the metabolic/ionic/electrical factors leading to sudden cardiac death and to the influence of various potentially therapeutic interventions on these changes. The projects in this program involve 16 members of the Departments of Medicine, Pathology, Biomedical Mathematics and Engineering and Biostatistics. The preparations used in the projects include isolated vesicles, single fibers, anesthetized open-chested acute animal preparations and man. Many of the studies will utilize ion selective electrodes and some will utilize pigs with and without von Willebrand's disease in which coronary atherosclerotic lesions will be induced. The individual projects will address the following problems: Project I--The relationship between platelet aggregation, coronary atherosclerosis and von Willebrand's factor in the production of acute ischemia. Project II--The effects of acute coronary occlusion and reperfusion on membrane ion permeation and transport. Project III--The effects of constituents of ischemia and antiarrhythmic drugs on the determinants of slow conduction in single fibers. Project IV--The relationship between conduction and excitability in human and canine artria. Project V--The electrophysiology of ventricular premature beats in man and in dog. It is our conviction that the integrated multidisciplinary approach which characterizes this Program Project will allow us to generate new information pertinent to the understanding of sudden cardiac death and will contribute to the desgign of interventions having the potential of preventing this catastrophic event.